PROJECT SUMMARY Unintended pregnancies among HIV-positive women have significant consequences for maternal morbidity and vertical transmission of HIV, and contraception prevents unintended pregnancies among the millions of HIV- positive women worldwide. Contraceptive implants are the most effective form of contraception available to HIV- positive in resource-limited settings. Implants, however, when combined with certain antiretroviral therapy (ART) regimens have reduced effectiveness leading to unintended pregnancies. Clinical and pharmacokinetic (PK) data now demonstrate drug-drug interactions between implants and efavirenz dosed at 600mg (EFV600) reducing implant effectiveness. The latest World Health Organization ART guidelines recommend the use of lower dose efavirenz at 400mg (EFV400) and dolutegravir in first line ART globally. Whether the same drug- drug interactions affect implant effectiveness with these newer ART regimens is unknown. Thus, critical gaps exist in current international and national HIV treatment and contraception guidelines regarding the concomitant use of ART and hormonal contraception. This project will close this important knowledge gap by prospectively assessing the PK and pharmacodynamics (PD) effects of EFV400 and dolutegravir on the plasma implant progestins (etonogestrel or levonorgestrel) and endogenous progesterone (a marker of ovulation suppression) concentrations. This proposal leverages an on- going PK study in Kenya evaluating implant progestin concentrations in women using EFV600. A total of 100 women on the different ART/implant combinations will undergo repeated plasma sampling up to 24 weeks after implant placement. Specifically, this project will determine if the PK/PD effects of EFV400 on implant progestin concentrations and proportion of women ovulating differ from those of EFV600 (Aim 1a) and of dolutegravir from EFV600 (Aim 1b). This project will also explore if pharmacogenetics (PG) polymorphisms in CYP450 enzymes known to affect progestin and ART metabolism will influence systemic concentrations of these hormones and ART regimens (Aim 2). This proposal directly addresses emerging concerns that different ART regimens could substantively and differentially impact contraceptive efficacy, and it explores this potential risk when these new regimens are just becoming available. It builds on the existing PK data in this field and expands it with PD and PG information. If our study demonstrates lack of improvement in progestin concentrations with EFV400 from EFV 600 and no effect on progestin concentrations with dolutegravir, these findings would support shifting ART guidelines to recommend dolutegravir-based ART as first-line ART?instead of alternative first-line?for women of reproductive age.